Anti-inflammatory 1 2 4-triazines

ABSTRACT

A SERIES OF SUBSTITUTED PYRIDAZINES AND 1,2,4-TRIAZINES HAVING ANTI-INFLAMMATORY ACTIVITY IS DESCRIBED. THESE COMPOUNDS ARE PREPARED FROM 3,6-DISTRIBUTED-S-TETRAZINES BY TREATMENT WITH A CYCLIC ENOL ETHER, AN ACETYLENIC AMINI, AN ACETYLENIC ETHER, A CYCLIC ENOL ESTER, OR AN IMINO ETHER.

United States Patent O 3,644,358 ANTI-INFLAMMATORY 1,2,4-TRIAZINESPatrick Rolfey, Camberley, and John Pomfret Verge,

Henley-on-Thames, England, assignors to Lilly Industries, Ltd., London,England No Drawing. Filed Jan. 14, 1970, Ser. No. 2,934 Claims priority,application Great Britain, Jan. 21, 1969, 3,364/ 69 Int. Cl. C07d 51/04,55/10 U.S. Cl. 260-248 AS 3 Claims ABSTRACT OF THE DISCLOSURE A seriesof substituted pyridazines and 1,2,4-triazines having anti-inflammatoryactivity is described. These compounds are prepared from3,6-disubstituted-s-tetrazines by treatment with a cyclic enol ether, anacetylenic amine, an acetylenic ether, a cyclic enol ester, or an iminoether.

BACKGROUND OF THE INVENTION It is known to react s-tetrazines withacyclic enol ethers and enamines, however, their reaction with cyclicenol ethers, acetylenic amines, acetylenic ethers, or cyclic enol estersto give novel substituted pyridazines have not previously beendescribed. Further, tetrazines have not been previously reacted withimino ethers to yield the novel 1,2,4-triazines described herein.

SUMMARY We have now discovered that novel pyridazines havinganti-inflammatory activity are obtained by treating a 3,6-disubstituted-s-tetrazine with a cyclic enol ether, an acetylenic amine,an acetylenic ether, or a cyclic enol ester when the 3 and 6substituents are a phenyl group or an alkoxycarbonyl group. In addition,novel 1,2,4-triazines having anti-inflammatory activity are obtainedwhen a 3,6- disubstituted-s-tetrazine is treated with an imino etherwhen the 3 and 6 substituents are an alkoxycarbonyl group. This methodof preparing 1,2,4-triazines is a novel synthetic method not previouslydescribed.

DESCRIPTION OF THE PREFERRED EMBODIMENT The novel pyridazines andtriazines of our invention are those having the following formula I 31R1 J l wherein:

Z is nitrogen or C-R 3,644,358 Patented Feb. 22, 1972 "ice each Rseparately is C -C alkyl or the two taken together with the nitrogen towhich they are attached form a piperidino or morpholino ring;

R is C C alkyl or benzyl; and

n is an integer of 2 to 3,

and the acid addition salts thereof.

Thus, when Z is nitrogen,-the compound is a novel 1,2,4- triazine. WhenZ is C-R the compound is a pyridazine. When Z is nitrogen the triazineis substituted in the 3 and 6 positions with an alkoxycarbonyl orcarboxamido group. When the compound is a pyridazine the 3 and 6substituents may be phenyl in addition to the groups described above.

The value of R varies depending upon the value of Z. For example, whenthe compound is a pyridazine, R is an alkyl, alkoxy, hydroxyal'koxy,hydroxyalkyl, or amino group. When the compound is a triazine, R is analkyl or phenyl group. When R is hydroxyalkyl it is possible for it toreact with the canboxylic ester in the 6-position to form a lactone.

When our novel compound is a pyridazine the carbon atom in the4-position of the ring may be unsubstituted or substituted 'with a C -Calkyl group. When R is amino it is dialkylamino or a cyclic amino suchas piperidino or morpholino.

Examples of C -C alkyl groups include methyl, ethyl, isobutyl,S-methylbutyl and n-hexyl. Examples of C -C alkoxy groups includemethoxy, ethoxy, n-butoxy and 3,3- dimethylbutoxy. Suitablehydroxyalkoxy groups are hydroxypropoxy and hydroxyethoxy. Examples ofhydroxyalkyl groups are hydroxyethyl and hydroxypropyl.

The starting material for the preparation of our novel pyridazines and1,2,4-triazines is an s-tetrazine of the formula wherein R and Q arephenyl or alkoxycarbonyl. This tetrazine is reacted with a cyclic enolether, an acetylenic amine, an acetylenic ether, a cyclic enol ester, oran imino ether as will be described in more detail below. The nature ofthe product obtained from the reaction is a function of the typecompound reacted with the tetrazine.

Cyclic enol ethers which may be used in the preparation of thepyridazines are those having the formula wherein X is oxygen or amethylene group and n is 2 or 3. The use of a cyclic enol ether of thistype results in the formation of a pyridazine wherein R in the above formula is hydroxyalkyl or hydroxyalkoxy, depending upon whether X. is amethylene group or oxygen.

Acetylenic amines and ethers are compounds of the formula wherein Q is CC, alkoxy or N(R and Q is hydrogen or C -C alkyl. The product from thisreaction is a pyridazine wherein R in the above formula is a C -C alkoxygroup or an amino group of the formula N(R and R in the above formula isa hydrogen or a C -C alkyl group.

A suitable cyclic enol ester is one having the formula wherein Q ishydrogen or C -C alkyl and m is 1 or 2. This reaction results in thepreparation of a pyridazine wherein R is a C -C alkyl group and R ishydrogen or a C -C alkyl group.

Reactions of the type we have described are known although they have notbeen used heretofore to prepare novel pyridazines of the type describedherein. These reactions are run at temperatures within the range ofabout to 100 C., and preferably within the range of about 20 to about 80C. The reaction is preferably carried out in an inert organic solventsuch as benzene, toluene, dioxane, or tetrahydrofuran. Reaction timesvary from about minutes to several days depending upon the reagentsemployed and the temperature of the reaction.

In addition to preparing novel pyridazines, we have found a novel methodfor the preparation of 1,2,4-triazines which also have anti-inflammatoryactivity. This novel synthetic method involves the treatment of atetrazine of the formula given above wherein R and Q are alkoxycarbonylwith an imino ether having tthe formula wherein R is C -C alkyl orphenyl and R is C C alkyl. The product of this reaction is a1,2,4-triazine of the above formula wherein Z is nitrogen, R and Q arealkoxycarbonyl, and R is C -C alkyl or phenyl.

Our synthesis of the triazines is conducted at a temperature of 0 to 100C., preferably at to 80 C., for a period of from about 15 minutes toseveral days. The reaction is preferably conducted in an inert solventsuch as benzene, toluene, dioxane, or tetrahydrofuran.

Once the pyridazines and triaziues have been prepared the alkoxycarbonylgroup can be converted to a carboxamido group by procedures well knownto those skilled in the art.

It is to be understood that those compounds of our invention wherein Ris hydroxyalkyl or hydroxyalkoxy may be converted to the correspondingesters using common esterification procedures. It is to be furtherunderstood that acid addition salts may be obtained from those compoundsof our invention containing basic amino groups in the molecule. Suchacid addition salts may be obtained by treatment of the amine with acidssuch as hydrochloric acid, sulfuric acid, acetic acid, propionic acidand phosphoric acid.

The following examples further illustrate the preparation of thecompounds of our invention. The toluene and dioxane used were freshlydistilled, the latter from sodium pellets. Molecular weights weredetermined on an A.E.I.M.S. 9 mass spectrometer.

EXAMPLE 1 3,6-diphenyl-4-(2'-hydroxyethoxy)pyridazine To a solutioncontaining 4 g. of 3,6-diphenyltetrazine and a trace of hydroquinone inml. of dry toluene was added 9 g. of dioxene. The solution was heatedunder reflux for two weeks when a thin layer chromatography examinationon silica gel using a mixture of benzene/ ethyl acetate (2:8) as thedeveloping agents indicated the absence of starting tetrazine. Onallowing the reaction mixture to cool, colorless crystals of3,6-diphenyl-4-(2-hydroxyethoxy)pyridazine separated which were removedby filtration, washed with a little toluene and dried.

Yield: 4.3 g. (78%); melting point 154-155" C. Analysis: 73.8% C, 5.8%H, 9.5% N. Calculated for C N N O C, H, N.

4 EXAMPLE 2 3 ,6 -diphenyl-4- (2'-acetoxyethoxy) pyridazine A solutioncontaining 1 g. of 3,6-diphenyl-4-(2'-hydroxyethoxy)pyridazine, 4 ml. ofpyridine and 8 ml. of acetic anhydride was heated at 90 C. for 3 hours.Removal of the solvent in vacuo and trituration of the resultant oilwith ether gave 3,6-diphenyl-4-(2-acetoxyethoxy)pyridazine as acolorless crystalline solid.

Yield: 800 mg. (70%); melting point 116-118 C. Analysis: 72.5% C, 5.8%H, 8.3% N. Calculated for C20H18N203: C., H, N.

A solution containing 200 mg. of 3,6-diphenyl-4-(2'-acetoxyethoxy)pyridazine in 10 ml. of ethanol and 5 ml. of 5 N sodiumhydroxide was heated under reflux for 3 hours. After cooling anddilution with 50 ml. of water the resultant white precipitate wasextracted into 50 ml. of chloroform. Evaporation of the organic layer invacuo and trituration of the residue with isopropanol gave 1000 mg. ofcrystalline material, M.P. 148-151 C. Recrystallization from benzenegave 54 mg. of pure hydrolysis product, M.P. 154-155 C. which wasindistinguishable from 3,6-diphenyl-4-(2' hydroxyethoxy)-pyridazine bythin layer chromatography, by I.R., UV. or N.M.R. spectroscopy or by amixed melting point determination.

EXAMPLE 3 3,6-diphenyl-4- (3 -hydroxypropyl) pyridazinetetrahydropyranyl ether To a solution containing 5 g. of3,6-diphenyltetrazine and a trace of hydroquinone in 75 ml. of drytoluene was added 15 ml. of 2,3-dihydropyran. The mixture was heatedunder reflux for 48 hours and evaporated in vacuo to give 6.8 g. of astraw colored oil which crystallized on standmg.

Recrystallization from ether gave pure 3,6-diphenyl-4-(3-hydroxypropyl)pyridazine tetrahydropyranyl ether.

Yield: 5.5 g. (71% melting point 104 C.

Analysis: 77.4% C., 6.9% H, 7.5% N; M, 374. Calculated for C d-1 N 077.1% C, 7.0% H, 7.5% N;

When a solution containing 1.07 g. (0.05 mole) of 3,6-

diphenyltetrazine and 0.45 g. (0.05 mole) of 2,3-dihydropyran in 15 ml.of toluene was heated under reflux for three weeks the only compoundswhich could be isolated were 3,6-diphenyl-4-(3 hydroxypropyl)pyridazine(ca. 25% yield) and unreacted 3,6-diphenyltetrazine.

EXAMPLE 4 3,6-dicarbomethoxy-4- (2-hydroxyethoxy) pyridazine To asolution containing 4 g. of 3,6-dicarbomethoxytetrazine in ml. of drydioxane was added 2.4 g. of dioxene at room temperature. The mixture wasstirred and the temperature increased to 60 C., when effervescence ofnitrogen commenced. After 30 minutes at this temperature the solutionwas light straw colored and the evolution of nitrogen ceased. Removal ofthe solvent in vacuo and trituration of the resultant oil with ethergave a crystalline solid, recrystallization of which from isopropanolgave 3,6-dicarbomethoxy-4-(2'hydroxyethoxy)- pyridazine.

Yield 4.1 g. (80%);melting point 109 C. Analysis: 46.6% C., 4.7% H,11.0% N. Calculated for C H N O 46.9% C, 4.7% H, 10.9% N.

EXAMPLE 5 3 ,6-dicarbomethoxy-4- (3 '-hydroxypropyl) pyridazine To astirred solution containing 2 g. of 3,6-dicarbomethoxytetrazine in 50ml. of dry dioxane was added 1.2 g. of 2,3-dihydropyran. An immediateexothermic reaction commenced with concomitant evolution of nitrogen andafter 2 hours the solution appeared almost colorless.

After standing overnight at room temperature the solvent was removed invacuo to give 3 g. of a light yellow oil which on trituration with ethergave 3,6-dicarbomethoxy- 4-(3-hydroxypropyl)pyridazine as a colorlesscrystalline solid.

Yield: 2.1 g. (80%);melting point 7274 C. Analysis: 52.1% C, 5.9% H,11.1% N. Calculated for CHI-114N205: C, H, N-

EXAMPLE 6 3,6-dicarbomethoxy-4-(3'-acetoxypropyl)pyridazine A solutioncontaining 400 mg. of 3,6-dicarbomethoxy- 4-(3-hydroxypropyl)pyridazine,2 ml. of pyridine and 5 ml. of acetic anhydride was heated at 90 C. for3 hours. Removal of the solvents in vacuo gave an oil which wasextracted into ml. of dichloromethane, washed with aqueous bicarbonate,water, and dried (MgSO TLC. of this solution on silica gel using amixture of benzene/ ethyl acetate (2:8) as the developing agentsindicated the absence of starting alcohol and the presence of only onereaction product (R 0.75). Removal of the solvent gave3,6-dicarbomethoxy-4-(3' acetoXypropyDpyridazine as a colorless oil.

Yield: 310 mg. (70%). M (found 296.1008; C H N O requires M 296.1008.

EXAMPLE 7 3,6-dicarbomethoxy-4-methyl-5-(N,N-diethylamino) pyridinehydrochloride.

To a solution containing 4 g. of 3,6-dicarbomethoxytetrazine in 75 ml.of dry dioxane at room temperature was slowly added a solution of 3 g.of 1-(N,Ndiethylamino)prop-l-yne in ml. of dioxane. An immediateexothermic reaction occurred and after 2 hours the solvent was removedin vacuo to give 6.5 g. of a yellow oil. This was dissolved in 100 ml.of dry ether and ethereal HCl added dropwise until precipitation of thehydrochloride was complete. Crystallization from iso-propanol/ ethergave pure 3,6-dicarbomethoxy-4-methyl-5-(N,N-diethylamino)pyridazinehydrochloride.

Yield: 5.4 g. (73%); melting point 98101 C. (decomposed). Analysis:49.6% C, 6.5% H, 13.2% N. Calculated for C H N O Cl: 49.2% C, 6.1% H.13.2%

EXAMPLE 8 3,6-diphenyl-4-methyl-5-(N,N-diethylamino)pyridazine To asolution containing 5 g. of 3,6-diphenyltetrazine in 60 ml. of drytoluene was added 4 g. of 1-(N,N-diethylamino)-prop-1-yne. After heatingunder reflux for 15 minutes evolution of nitrogen ceased and thesolution became light yellow. Removal of the solvent in vacuo gave anoil which solidified on trituration with ether. Crystallization fromiso-propanol gave 3,6-diphenyl-5- methyl 5 (N,N diethylamino)pyridazineas colorless needles.

Yield: 4.8 g. (65%); melting point 120-12l C. Analysis: 79.7% C, 7.4% H,13.4% N. Calculated for C H N 79.4% C, 7.4% H, 13.3% N.

EXAMPLE 9 3,6-dicarbomethoxy-4-ethoxypyridazine To a solution containing1 g. of 3,6-dicarbomethoxytetrazine in 15 ml. of dry dioxane was added0.4 g. of ethoxyacetylene in 5 ml. of dry dioxane. The solution was keptat 45 C. for 3 hours and finally heated under reflux for minutes.Removal of the solvent gave a light orange oil which crystallized onstanding. Recrystallization from iso-propanol/petroleum ether (B.P. -60)gave 3,6-dicarbomethoxy-4-ethoxypyridazine.

Yield: 700 mg. (63%); melting point 72-75 C.

6 EXAMPLE 10 3,6-dicarbomethoxy-4-methyl-5-(2-hydroxyethyl) pyridazineTo a solution containing 5 g. of 3,6-dicarbomethoxytetrazine in ml. ofdioxane was added a solution of 2.4 g. of 5-methyl-2,3-dihydrofuran in24 ml. of dioxane. After the initial exothermic reaction had subsidedthe mixture was warmed to C. for 2%. hours. Removal of the solvent invacuo gave an oil which solidified on trituration with ether. Pure3,6-dicarbomethoxy-4-methyl- 5-(2-hydroxyethyl)pyridazine was obtainedby crystallization from methanol/ ether.

Yield: 4.9 g. (77%), melting point l07 C. Analysis: 52.2% C, 5.6% H,11.2% N. Calculated for CHI-114N205: C, H, N.

EXAMPLE 11 3,6-dicarbomethoxy-4,5-dirnethylpyridazine To a solutioncontaining 1 g. of 3,6-dicarbomethoxytetrazine in 15 ml. of dioxane wasadded a solution of 0.6 g. of angelica lactone in 5 ml. of dioxane. Themixture was heated at between 6070 C. for 4 hours and the solventsremoved in vacuo to give 1.5 g. of a yellow oil. Trituration withisopropanol gave 400 mg. of a crystalline product, M.P. 85-90 C.Recrystallization from isopropanol (with charcoaling) gave colorlessneedles of 3,6-dicarbomethoxy-4,S-dimethylpyridazine.

Yield: 200 mg. (18%); melting point 101102 C. Analysis: 53.6% C, 5.0% H,12.6% N; M 224. Calculated for C H N O 53.6% C, 5.4% H, 12.5% N; M 224.

EXAMPLE 12 3,6-dicarbomethoxy-5-methyl-1,2,4-triazine To a stirredsolution containing 5 g. of 3,6-dicarbomethoxytetrazine in 75 ml. ofdioxane was slowly added 2.25 g. of ethyl acetimidate in 25 ml. ofdioxane at room temperature. The mixture was then stirred at 60 C. for10 hours when the color had changed to yellow-green.

A T.L.C. examination on silica gel using a mixture of benzene/ethylacetate (2:8) as the developing agents indicated the presence of onemajor reaction product, R 0.8. Removal of the solvent in vacuo gave 51g. of an oil which was chromatographed on a column (80x3 cm.) of silicagel (100-200 mesh). Initial development with a mixture of ethylacetate/benzene (2:3) eluted a bright yellow impurity. The majorreaction product was eluted as a light yellow hand using a mixture ofethyl acetate/benzene (1:1) as eluant. Removal of the solvents from thisfraction gave an oil which on trituration with cold ether gave3,6-dicarbomethoxy-5-methyl-1,2,4-tria- Zine as a light yellowcrystalline solid.

Yield: 630 mg. (13%); melting point 82-83 C. Analysis: 45.4% C, 4.5%; H,20.0% N; M 211.

Calculated for C H N O 45.5% C, 4.3% H, 19.9% N:

EXAMPLE 13 3,6-dicarbomethoxy-S-phenyl-1,2,4-triazine Yield: 190 mg.(27%); melting point l13 C. Analysis: 57.3% C, 4.1% H, 15.6% N; M, 273.

7 Calculated for C H N O 57.2% C, 4.1% H, 15.4%

N; M, 273. EXAMPLE 14 3-oxo-7-methyl-8-carbomethoxy-5 ,6-dihydropyrano[3 ,4c1pyridazine A solution of 200 mg. of 3,6-dicarbomethoxy-4-methyl-5-(2-hydroxyethyl)pyridazine in ml. of dry methanol was saturated withHCl gas and heated under reflux for 15 minutes. The solvent was removedin vacuo and the resultant oil crystallized from iso-propanol to give3-oxo- 7-methyl 8 carbomethoxy 5,6 dihydropyrano[3,4c] pyridazine ascolorless needles.

Yield: 170 mg. (96%); melting point l6ll63 C. Analysis: 54.1% C, 4.7% H,12.6% N. Calculated for C10H10N2041 C, H, N.

The novel compounds of our invention exhibited antiinflammatoryactivity. They may be formulated in dosage forms for both, oral andparenteral administration. The formulation of compounds exhibiting suchactivity in association with pharmaceutical carriers or diluents is wellknown.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms the activecompound is admixed with at least one inert diluent such as sucrose,lactose, or starch. Such dosage forms can also contain additionalsubstances other than inert diluents, for example, lubricating agentssuch as magnesium stearate. In the case of capsules, tablets and pillsthe dosage forms may also contain buffer-ing agents. Tablets and pillscan additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water.Besides inert diluents, such compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or nonaqueous solutions, suspensions, oremulsions. Examples of nonaqueous solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils such as olive oil, andinjectable organic esters such as ethyl oleate. Such dosage forms mayalso include adjuwants such as preserving, wetting, emulsifying, anddispersing agents. They may also be manufactured in the form of sterilesolid compositions which can be dissolved in sterile water or some othersterile injectable medium immediately prior to use.

The dosage of active ingredient to be administered varies with thedegree of activity of the compound being employed. Generally, dosagelevels of 50 to 150 ing/kg. of body weight are administered to mammalsfrom one to three times daily to obtain effective relief ofinflammation, pain and fever.

The anti-inflammatory activity of a representative number of compoundsof our invention was demonstrated in the Well-known carrageenin testwherein the measure of activity is the reduction in swelling of aninflamed mouse paw. A reduction of or better is considered to besignificant 1n this test. The results of the test are shown in thefollowing table. In each test the animal was given two doses at thelevel indicated. Administration was oral.

Dosage, Perccntre- Compound ing/kg. (luction3,fi-dicarbomethoxy-S-methyl-l,ZA-triazinc 100 373,6-dipheny1-4-(2-hydroxyethoxy)pyi'idazine 100 323,6-bis(N-benzylcarboxamido)-4-(3-hydroxypropyDpyridazine 5O3,6-diphenyl-4-methyl-5-(N,N-diethylumiuo) 7 pyridazine 100 88. 5

8 We claim: 1. A compound selected from the group consisting of acompound of the formula:

R is C -C alkoxy or NHR R is C -C alkyl or benzyl; and thepharmacologically acceptable acid addition salts thereof.

2. A compound as in claim 1 wherein R is COCH;

and R is methyl.

3. A method for the preparation of 1,2,4-triazine having the formulawhich comprises treating a 3,6-disubstitutecl-s-tetrazine having theformula with an imino ether having the formula at a temperature withinthe range of 0 to C., wherein in the formulas R and Q are R is C -Calkyl or phenyl; R is C -C alkoxy; and R is C -C alkyl.

References Cited UNITED STATES PATENTS 3,428,635 2/1969 Trepanier et a1260--248 JOHN M. FORD, Primary Examiner US. Cl. X.R.

